Extracapillary glomerulonephritis is a proliferative glomerulonephritis such as rapidly progressive glomerulonephritis and collapsing glomerulopathy. The term “extracapillary proliferation” describes proliferation of glomerular epithelial cells, namely podocytes and parietal epithelial cells.
Glomerular injury during crescentic rapidly progressive glomerulonephritis (RPGN) manifests as a proliferative histological pattern with accumulation of inflammatory cells, fibrin and proliferation of intrinsic glomerular cells in Bowman's space (“crescents”) and rapid deterioration of renal function within days or months.
Rapidly progressive glomerulonephritis (RPGN) complicating necrotizing crescentic glomerulonephritis represents the most severe form of glomerular involvement and can occur in the setting of various immunological disorders, including anti-glomerular basement membrane (anti-GBM), ANCA-associated vasculitis, or immune complex diseases like lupus and infectious diseases (1, 2). Strikingly, crescent formation seems to occur downstream to inflammatory injury of the glomerulus in a way that is relatively similar whatever the causative immunological disorder. The explanation for this observation might be that the pathogenesis of RPGN is not restricted to the action of inflammatory cells and immune mediators. It has become clear that proliferation of parietal epithelial cells (3) and podocytes (4) plays a key role in crescent formation. Studies in human biopsies (5) and in a mouse model (6) demonstrated that podocytes dysregulated in RPGN, losing their original cell markers and switching to a proliferative phenotype. Convincing evidence for podocyte involvement in RPGN also came from a seminal study in a murine model where podocyte-specific deletion of the Vhl gene resulted in proliferation of podocytes, crescent formation and rapid onset of renal failure (7). The inventors recently demonstrated that the activation of the epidermal growth factor receptor (EGFR) in podocytes by de novo expression of the heparin-binding epidermal growth factor-like growth factor (HB-EGF) also plays a major role in the development of RPGN (8). Numerous proteins and signaling pathways can be activated downstream to EGFR activation, including proteins of the signal transducer and activator of transcription (STAT) family, namely STAT5 (9) and STAT3 (10). STAT3-SH2 domain can directly bind phosphorylated EGFR on tyrosine 1068 and tyrosine 1086 (11). STAT3 is a known transducer of signals from growth factors and cytokines and plays important roles in development, cell growth, prevention of apoptosis, proliferation and inflammation (12).
Accordingly, there is a need to develop new drugs that will be suitable for preventing or treating rapidly progressive glomerulonephritis (RPGN). In this way, it has been suggested that characterization of new compounds for treatment of RPGN may be highly desirable.
Collapsing glomerulopathy (CG) is a different kidney disease and is a morphologic variant of focal segmental glomerulosclerosis (FSGS) characterized by segmental and global collapse of the glomerular capillaries, marked hypertrophy and hyperplasia of podocytes, and severe tubulointerstitial disease (Albaqumi M, Barisoni L. Current views on collapsing glomerulopathy. J Am Soc Nephrol. 2008 July; 19(7):1276-81. PMID:18287560; Schwimmer J A, Markowitz G S, Valeri A, Appel G B. Collapsing glomerulopathy. Semin Nephrol. 2003 March; 23(2):209-18. PMID:12704581). The pathogenesis of collapsing focal segmental glomerulosclerosis (FSGS) in patients not infected with HIV is not clear. As with HIV-associated nephropathy, the underlying pathogenic event appears to be a severe insult to the integrity and biology of the glomerular visceral (podocytes) and parietal epithelial cells. This damage ultimately results in cellular dedifferentiation and proliferation of these glomerular epithelial cells accompanied by a profound loss of the glomerular filtration barrier function as seen in RPGN. Activation of the STAT family, namely STAT3, has been shown in HIV (human immunodeficiency virus)-associated nephropathy, a common form of CG (He J C, Husain M, Sunamoto M, D'Agati V D, Klotman M E, Iyengar R, Klotman P E. Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1,2 pathways. J Clin Invest. 2004 September; 114(5):643-51. PMID:15343382).
Accordingly, the characterization of new compounds for treatment of CG is highly desirable.
MicroARNs (miRNAs) are endogenous small nucleotide single-stranded non coding RNA that can disrupt protein expression by inducing translation inhibition and mRNA degradation. Recent evidence indicates that miRNA could have a pivotal role in renal disorders (13). Because STAT3 can activate the expression of various miRNAs in several proliferative disorders (14-16) and a study has found a highly conserved STAT3-binding site in the promoter region of the miR-17/92 gene in non kidney cell (17), the inventors have studied the expression of miR-92 in STAT3 modulation model.
There is no disclosure in the art of the role of miR-92a in rapidly progressive glomerulonephritis (RPGN) (or necrotizing crescentic glomerulonephritis) nor in collapsing glomerulopathy (CG), and the use of miR-92a inhibitor compounds in the prevention or treatment of RPGN and CG.